Update on Toxic Myopathies

Abstract

The toxic myopathies are a clinically and pathologically diverse group of disorders that can be caused by a variety of therapeutic agents used in clinical practice, as well as various venoms and other biological toxins. The most important iatrogenic causes are the statin and fibrate cholesterol-lowering agents that can cause a severe necrotizing myopathy and acute rhabdomyolysis and myoglobinuria. The current update focuses on the mechanisms of statin myotoxicity and the importance of genetic predisposing factors for statin myopathy, as well as the recently described form of necrotizing autoimmune myopathy, which is associated with antibodies to the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme and is responsive to aggressive immunotherapy. Mitochondrial myopathies associated with antiretroviral agents and the pyrimidine nucleoside analogue clevudine, and recent reports of myopathies caused by ingestion of red yeast rice and toxic species of mushrooms are also discussed.

NMR evaluation of total statin content and HMG-CoA reductase inhibition in red yeast rice (Monascus spp.) food supplements

“…Red yeast rice is expected to have the adverse effects of its constituent lovastatin, including an increased risk of myopathy [14-18], acute rhabdomyolysis [19], symptomatic hepatitis [20] and anaphylactic reactions [21]. Drug interactions may influence liver enzyme expression leading to a lower clearance and elevated plasma concentration of lovastatin ( e.g ., by inhibition of cytochrome P450 enzyme CYP3A4) [19,22].…”

“…Drug interactions may influence liver enzyme expression leading to a lower clearance and elevated plasma concentration of lovastatin ( e.g ., by inhibition of cytochrome P450 enzyme CYP3A4) [19,22]. When lovastatin is administered with food, the intestinal absorption may be increased by about 50%, while pectin and oat bran may decrease its absorption [22-24].…”

Pathology of Adult and Paediatric Mitochondrial Myopathies

“…Increased numbers of COX-deficient and SDH-positive fibres within atrophic perifascicular zones are a common feature in dermatomyositis 138 . Histochemical and biochemical OXPHOS dysfunction can be induced by the toxic effects of a range of drugs on mitochondrial respiration, including antiretroviral agents and statins 139 , antiepileptics such as valproate, immunosuppressant and cytotoxic chemotherapeutic agents 13,14 . Accumulation of multiple mtDNA deletions and tRNA point mutations has been observed in ageing human tissues 140,141 with highest levels in post-mitotic tissues such as brain and skeletal muscle.…”

Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century?

“…In addition to the spectrum of reversible muscle pathology, a chronic inflammatory autoimmune necrotizing myositis requiring immunosuppression has been described in association with statin use. The syndrome is very rare, but has recently been recognized to be associated with the presence of antibodies to the 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase enzyme [13,14]. These antibodies are rare in the absence of both this phenotype of myositis and statin exposure [15].…”

“…Statins and their active metabolites are competitive substrates of HMG-CoA reductase enzyme, thereby inhibiting the conversion of HMGCoA to mevalonic acid. Mevalonic acid, being a precursor of isoprenoids, is required for RNA transcription and posttranslational lipid modification of proteins [13,32].…”